Effect of monoamine receptor agonists and antagonists on cyclic AMP accumulation in human cerebral cortex slices.

In human cerebral cortex slices noradrenaline, isoproterenol (a beta-adrenergic agonist), dopamine, apomorphine (a dopaminergic agonist), and serotonin stimulated cyclic AMP formation: noradrenaline greater than or equal to isoproterenol greater than dopamine = apomorphine = serotonin. Clonidine (and alpha-adrenergic agonist) was ineffective in stimulating cyclic AMP formation in temporal cortex slices. The stimulatory effect of noradrenaline and isoproterenol was blocked by propranolol (a beta-adrenergic blocker) but not by phentolamine (an alpha-adrenergic blocker). Pimozide (a selective dopaminergic antagonist) inhibited the increase of cyclic AMP formation induced by dopamine or apomorphine but not that induced by noradrenaline, isoproterenol, or serotonin. Neither propranolol or phentolamine had any effect on dopamine- or serotonin-stimulated cyclic AMP formation. Chlorpromazine blocked the increase of cyclic AMP formation induced by noradrenaline, dopamine or serotonin, while cyproheptadine, a putative central serotonergic antagonist, was ineffective. These observations suggest that there may be at least two monoamine-sensitive adenylate cyclases in human cerebral cortex which have the characteristics of a beta-adrenergic and a dopaminergic receptor, respectively, and also possibly a serotonergic receptor.     

Serum parathyroid hormone concentration measured by highly sensitive assay in post-thyroidectomy hypocalcemia of patients with Graves' disease

To investigate the role of parathyroid function in transient hypocalcemia after subtotal thyroidectomy for Graves' disease, the serum parathyroid hormone (PTH) concentration and nephrogenous (N) cAMP were measured in 16 patients before and after surgery. Serum PTH was measured with two commercially available kits (PTH-M, PTH-C), PTH-M is a recently developed highly sensitive assay using an antibody recognizing the mid-portion of human PTH and a synthetic 125I-tyr45-human PTH (43-68) as a radioligand. One of the 16 patients had severe clinical tetany and had a markedly lower PTH-M concentration and NcAMP after thyroidectomy. However, no significant change in serum PTH-M, PTH-C and NcAMP were observed in the other patients, although their serum calcium (Ca) concentrations decreased significantly. The Data were analyzed by dividing the patients according to the change in serum Ca or PTH. Serum PTH-M and PTH-C significantly decreased in 4 patients whose serum Ca clearly decreased after surgery. Serum Ca on the first postoperative day was significantly lower in patients whose serum PTH decreased after thyroidectomy than in patients whose serum PTH did not. Furthermore, the serum Ca concentration was significantly correlated with PTH-M, and with NcAMP on the third postoperative day. These data proved that hypofunction of the parathyroid gland is important in transient hypocalcemia after subtotal thyroidectomy for Graves' disease. The pathogenetic mechanism of transient hypocalcemia was discussed in comparison with the data from a patient who had overt parathyroid injury.     

Parathyroid hormone stimulates protein kinase C but not adenylate cyclase in mouse epidermal keratinocytes.

Intact human parathyroid hormone, hPTH [1-84], and the hPTH [1-34] fragment stimulated membrane-associated protein kinase C (PKC) activity in immortalized (but still differentiation-competent) murine BALB/MK-2 skin keratinocytes. Unexpectedly, the hormone and its fragment did not stimulate adenylate cyclase. The failure of PTH to stimulate adenylate cyclase activity was not due to the lack of a functioning receptor-cyclase coupling mechanism because the cells were stimulated to synthesize cyclic adenosine monophosphate (cyclic AMP) by the beta-adrenergic drug isoproterenol. Thus, skin keratinocytes seem to have an unconventional PTH receptor that is coupled to a PKC-activating mechanism but not to adenylate cyclase. These observations suggest that normal and neoplastic skin keratinocytes respond to the PTH-related peptide that they make and secrete.     

Alterations in the subcellular distribution of p21ras-GTPase activating protein in proliferating rat acinar cells.

Rat parotid acinar cells undergo transient proliferation in response to chronic administration of the beta-adrenergic agonist isoproterenol or epidermal growth factor (EGF). Treatment with these agents caused an increase in tyrosine phosphorylation of p21ras-GTPase activating protein (GAP). This phosphorylation event was accompanied by a redistribution of the protein from the plasma membrane to internal membrane compartments. Separation of subcellular membranes revealed increased GAP associated with a low density population of vesicles concomitant with growth stimulation as well as to the nuclear membrane, but not the nucleoplasm. Upon cessation of hyperplasia induced by isoproterenol, phosphorylated GAP present in the plasma membrane returned to control cell levels.     

beta-adrenergic responsiveness of rats treated chronically with isoproterenol

The effect of chronic administration of isoproterenol on isoproterenol-induced thirst and isoproterenol-induced changes in heart rate and selected organ weights of male rats was studied. Administration of 25 micrograms isoproterenol/kg, s.c., in saline daily for 10 days was accompanied by a significant attenuation of the characteristic increase in water intake following a challenging dose of isoproterenol (25 micrograms/kg, s.c.) on the 11th day. Administration of 25 micrograms isoproterenol/kg, s.c., every 2nd, 3rd or 4th day for 10 days was without significant effect on water intake following isoproterenol (25 micrograms/kg, s.c.) on the 11th day. Administration of 25 micrograms isoproterenol/kg, s.c., every day for 10 days led to a slight increase in cardiac responsiveness to a challenging dose of isoproterenol (25 micrograms/kg) on the 11th day. Chronic treatment with this low dose of isoproterenol for 10 days was also accompanied by a significant increase in the ratio of heart weight to body weight but no significant changes in the ratio of kidney, adrenal, thyroid, spleen, or interscapular brown fat to body weight. Thus, daily administration of the beta-adrenergic agonist isoproterenol for 10 days can alter beta-adrenergic responsiveness in the rat with beta 1 (heart rate) and beta 2 (thirst) mediated responses showing opposite effects. In addition, the results suggest that tests of beta-adrenergic responsiveness must be assessed in terms of the frequency of administration of the agonist.     

Parathyroid hormone release is not associated with acute sympathetic arousal in goats.

Physiological activation of the sympathetic adrenomedullary (SAM) axis following both thermal and non thermal stress was assessed by changes in serum norepinephrine, glucose and/or protein as well as indices of peripheral blood flow. The occurrence of elevated serum parathyroid hormone (PTH) did not reliably reflect SAM activation as might be predicted from pharmacological studies that document a beta adrenergic receptor mechanism in the parathyroid gland that mediates catecholamine stimulated release of PTH into the circulation. The beta agonist isoproterenol at 1 microgram/min for 60 min did produce a transient increase in serum PTH at 20 min. Overall, the data raise doubts about the physiological significance of the adrenergic receptor in the parathyroid gland. Significant increases in serum PTH of 67% and 109% above basal respectively were seen following ruminal loading with cold and thermoneutral water. Associated with the PTH change were increased serum phosphorus and elevated or constant serum protein and serum total calcium.     

Inhibition of parathyroid hormone-responsive adenylate cyclase in clonal osteoblast-like cells by transforming growth factor alpha and epidermal growth factor

The effects of transforming growth factor alpha (TGF-alpha) and epidermal growth factor (EGF) on parathyroid hormone (PTH)-responsive adenylate cyclase were examined in clonal rat osteosarcoma cells (UMR-106) with the osteoblast phenotype. Recombinant TFG-alpha and EGF incubated with UMR-106 cells for 48 h each produced concentration-dependent inhibition of PTH-responsive adenylate cyclase, with maximal inhibition of 38-44% at 1-3 ng/ml of either growth factor. TGF-alpha and EGF also inhibited beta-adrenergic agonist (isoproterenol)-stimulated adenylate cyclase by 32%, but neither growth factor affected enzyme response to prostaglandin or basal (unstimulated) activity. Nonreceptor-mediated activation of adenylate cyclase by forskolin and cholera toxin was inhibited 18-20% by TGF-alpha and EGF. Pertussis toxin augmented PTH-stimulated adenylate cyclase, suggesting modulation of PTH response by a functional inhibitory guanine nucleotide-binding regulatory component of the enzyme. However, pertussis toxin had no effect on TGF-alpha inhibition of PTH response. Growth factor inhibition of PTH response was time-dependent, with maximal inhibition by 4-12 h of TGF-alpha exposure, and was reduced by prior treatment of UMR-106 cells with cycloheximide. TGF-alpha was not mitogenic for UMR-106 cells. The results indicate that TGF-alpha and EGF selectively impair PTH- and beta-adrenergic agonist-responsive adenylate cyclase of osteoblast-like cells. Growth factor inhibition of adenylate cyclase may be exerted at the receptor for stimulatory agonist and at nonreceptor components excluding pertussis toxin-sensitive guanine nucleotide-binding regulatory proteins. The inhibitory action of growth factors may also require protein synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiovascular effects of bPTH-(1-34) and isoproterenol in the frog, Rana tigrina.

1. The cardiovascular effects of bovine parathyroid hormone fragment [bPTH-(1-34)] and isoproterenol (ISO) on frog (Rana tigrina) isolated atria and helical strips of blood vessels were examined since PTH produces a beta-adrenergic-like effect in the mammal. 2. Data showed that both bPTH-(1-34) and ISO were vasorelaxant in KCl and arginine vasoctocin (AVT) preconstricted dorsal aorta, iliac and femoral arteries. 3. They both relaxed extracellular calcium-dependent contrations. 4. There was no additive nor synergistic effect between them in AVT preconstricted strips. 5. Both bPTH-(1-34) and ISO were positively inotropic but differed in their chronotropic effects, being negative and positive. 6. In the tiger frog, bPTH-(1-34) shows beta-adrenergic like contractile responses in both the cardiac and vascular smooth muscle as in the mammal, but not in the heart rate.     

Regulation of hormone secretion and cytosolic Ca2+ by extracellular Ca2+ in parathyroid cells and C-cells: role of voltage-sensitive Ca2+ channels

The two dihydropyridine enantiomers, (+)202-791 and (-)202-791, that act as voltage-sensitive Ca2+ channel agonist and antagonist, respectively, were examined for effects on cytosolic Ca2+ concentrations ([Ca2+]i) and on hormones secretion in dispersed bovine parathyroid cells and a rat medullary thyroid carcinoma (rMTC) cell line. In both cell types, small increases in the concentration of extracellular Ca2+ evoked transient followed by sustained increases in [Ca2+]i, as measured with fura-2. Increases in [Ca2+]i obtained by raised extracellular Ca2+ were associated with a stimulation of secretion of calcitonin (CT) and calcitonin gene-related peptide (CGRP) in rMTC cells, but an inhibition of secretion of parathyroid hormone (PTH) in parathyroid cells. The Ca2+ channel agonist (+)202-791 stimulated whereas the antagonist (-)202-791 inhibited both transient and sustained increases in [Ca2+]i induced by extracellular Ca2+ in rMTC cells. Secretion of CT and CGRP was correspondingly enhanced and depressed by (+)202-791 and (-)202-791, respectively. In contrast, neither the agonist nor the antagonist affected [Ca2+]i and PTH secretion in parathyroid cells. Depolarizing concentrations of extracellular K+ increased [Ca2+]i and hormone secretion in rMTC cells and both these responses were potentiated or inhibited by the Ca2+ channel agonist or antagonist, respectively. The results suggest a major role of voltage-sensitive Ca2+ influx in the regulation of cytosolic Ca2+ and hormones secretion in rMTC cells. Parathyroid cells, on the other hand, appear to lack voltage-sensitive Ca2+ influx pathways and regulate PTH secretion by some alternative mechanism.     

Clinical heterogeneity of pseudohypoparathyroidism: from hyper- to hypocalcemia

Pseudohypoparathyroidism (PHP) is a rare inherited syndrome characterized by parathyroid hormone (PTH) resistance and is frequently associated with Albright's hereditary osteodystrophy and resistance to other cAMP-mediated hormones. The usual neonatal presentation is mild primary hypothyroidism secondary to resistance to thyroid-stimulating hormone; hypocalcemia usually develops after age 3-5 years. This work describes the diversity in the clinical expression and course of PHP, with emphasis on calcium levels by age and treatment, in 8 children under long-term follow-up at our pediatric tertiary center. The calcium levels at presentation ranged from transient neonatal hypocalcemia to infantile hypercalcemia to childhood/adolescence hypocalcemia. Interestingly, relative hypocalciuria at diagnosis and during therapy, in the presence of renal PTH resistance, was the rule. These findings indicate that transient neonatal hypocalcemia associated with other clinical features or a family history of PHP may be a flag for clinicians to screen for PTH resistance later in life. In addition, PTH resistance may be missed by surveying calcium levels only; thus the PTH levels have to be checked as well. In addition, the recommendation for patients with hypoparathyroidism that strict low-normal calcium levels be maintained during therapy in order to prevent hypercalciuria is probably not applicable in PHP.     

Effects of beta-adrenergic stimulation on 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine-mediated vasoconstriction and glycogenolysis in the perfused rat liver

The beta-adrenergic agonist isoproterenol inhibited the glycogenolytic response of platelet-activating factor (AGEPC, 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine) in perfused livers derived from fed rats. AGEPC-stimulated hepatic vasoconstriction, measured by increases in portal vein pressure, also was inhibited by prior isoproterenol infusion. Isoproterenol-mediated inhibition of these hepatic responses to AGEPC was not apparent when isoproterenol (10 microM) was coinfused with the beta-receptor antagonist propranolol (75 microM) or when isoproterenol was replaced with the alpha-adrenergic agonist phenylephrine (10 microM). alpha-Agonist-induced glycogenolysis and vasoconstriction in the perfused liver was unaffected by isoproterenol infusion. Glucagon (2.3 nM) had no effect on the glycogenolytic or vasoconstrictive responses of the liver to AGEPC despite the fact that glucagon increased hepatic cAMP levels to a far greater extent than isoproterenol. Additionally, inhibition of the hepatic responses to AGEPC by isoproterenol occurred in perfused livers from mature rats (i.e. greater than 300 g) in which liver parenchymal cells lack functional beta-adrenergic receptors. The data presented in this study illustrate a specific inhibition of AGEPC-induced hepatic glycogenolysis and vasoconstriction by beta-adrenergic stimulation of the perfused liver. This inhibition appears to be mediated by interaction of isoproterenol with nonparenchymal cells within the liver. These findings are consistent with the concept that AGEPC stimulates hepatic glycogenolysis by an indirect mechanism involving hepatic vasoconstriction.     

Prediction of the outcome of postoperative hypocalcemia in Graves' disease.

Symptomatic hypocalcemia sometimes follows subtotal thyroidectomy for Graves' disease. Irreversible damage to the parathyroids contributes to permanent hypocalcemia and the mechanism for a transient hypocalcemia is thought to be different from that of a permanent one. However, sensitive assays for parathyroid hormones (PTH), which had recently become available, revealed that levels of PTH decrease in patients with transient hypocalcemia. In order to differentiate a prolonged hypocalcemia from a transient one, calcium and inorganic phosphate concentrations in serum as well as in urine, and whole molecule-PTH levels were determined in 18 Graves' disease patients with postoperative hypocalcemia just after the initial symptoms for hypocalcemia appeared. In 13 patients, medication was withdrawn within one month since serum calcium levels had returned to normal (transient hypocalcemia). In five other patients, medication was required for six months or more to maintain normocalcemia (prolonged hypocalcemia). The same parameters were determined after surgery in eight Graves' disease patients without hypocalcemia. Urinary inorganic phosphate concentrations in patients with prolonged hypocalcemia (0.02 +/- 0.01 mmol/mmol Cr) were significantly lower (P less than 0.01) than those in patients with transient hypocalcemia (1.59 +/- 1.59 mmol/mmol Cr) or those in control patients (1.27 +/- 0.70 mmol/mmol Cr). Preoperative concentrations of calcium and inorganic phosphate in serum and urine, and serum alkaline-phosphatase activities were also determined. However, there were no significant differences in these parameters between patients with prolonged and those with transient hypocalcemia. It is concluded that prolonged hypocalcemia is discriminated from the transient type by determining the urinary inorganic phosphate at the time of appearance of the initial symptoms for hypocalcemia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Protection against alloxan-induced diabetes in mice by stimulation of alpha 2-adrenergic receptors

A single intravenous injection of alloxan in mice induced hyperglycemia in a dose dependent fashion. This diabetogenic action of alloxan was prevented by a single intraperitoneal injection of the alpha 2-adrenergic agonists, i.e. oxymetazoline, clonidine or epinephrine 40 min prior to the injection of alloxan. The alpha 1-adrenergic agonists, i.e. methoxamine and phenylephrine, and a beta-adrenergic agonist, isoproterenol, failed to prevent the diabetogenic action of alloxan. The inhibitory effect of clonidine on alloxan-induced diabetes was antagonized by yohimbine or phentolamine, but not by prazosin. Although alpha 2-adrenergic agonists caused a transient hyperglycemia at the time of alloxan administration (40 min after the administration of alpha 2-adrenergic agonists), the plasma glucose level at the time of alloxan injection did not correlate with the anti-diabetogenic effect of alpha 2-adrenergic agents. These results clearly demonstrate that the alpha 2-adrenergic mechanism which inhibits insulin release from pancreatic B cells prevented the diabetogenic action of alloxan in mice.     

Beta-adrenergic stimulation of volume-sensitive chloride transport in lamprey erythrocytes

We measured the effects of a beta-adrenergic agonist, isoproterenol, on chloride transport and volume regulation of lamprey (Lampetra fluviatilis) erythrocytes in isotonic (288 mosm L(-1)) and hypotonic (192 mosm L(-1)) medium. Isoproterenol at a high concentration (10(-5) M) did not influence chloride transport in isotonic medium but markedly increased chloride fluxes in hypotonic conditions: unidirectional flux increased from 100 mmol kg dcw(-1) h(-1) in the absence to 350 mmol kg dcw(-1) h(-1) (dcw=dry cell weight) in the presence of isoproterenol. Simultaneously, the half-time for volume recovery decreased from 27 to 9 min. Isoproterenol caused an increase in cellular cyclic AMP (cAMP) concentration. The stimulation of chloride transport in hypotonic conditions could be induced by application of the permeable cAMP analogue, 8-bromo-cyclic AMP, suggesting that the effect of beta-adrenergic stimulation on chloride transport occurs downstream of cAMP production. As isoproterenol did not affect unidirectional rubidium fluxes in hypotonic conditions, the transport pathway influenced by beta-adrenergic stimulation is most likely the swelling-activated chloride channel. Because the beta-adrenergic agonist only influenced the transport in hypotonic conditions despite the fact that cAMP concentration also increased in isotonic conditions, the activation may involve a volume-dependent conformational change in the chloride channel.     

Secretion of gastric mucus phospholipids in response to beta-adrenergic G protein-coupled receptor activation is mediated by SRC kinase-dependent epidermal growth factor receptor transactivation.

Recent advances in understanding the nature of cellular responses mediated by G protein-coupled receptor (GPCR) activation indicate that integration of the converging regulatory signals into functional cellular pathways requires epidermal growth factor receptor (EGFR) transactivation. In this study, we report that G protein-coupled beta-adrenergic receptor activation leading to stimulation in gastric mucus phospholipid secretion occurs with the involvement of EGFR. Using [14C]choline-labeled gastric mucosal cells in culture, we show that stimulatory effect of beta-adrenergic agonist, isoproterenol, on phospholipid release was subject to a dose-dependent suppression by EGFR kinase inhibitor, PD153035, as well as wortmannin, a specific inhibitor of PI3K. Both inhibitors, moreover, caused the reduction in the gastric mucosal cell phospholipid secretory responses to beta-adrenergic agonist-generated second messenger, cAMP as well as adenyl cyclase activator, forskolin. The gastric mucosal phospholipid secretory responses to isoproterenol, furthermore, were inhibited by PP2, a selective inhibitor of tyrosine kinase Src responsible for ligand-independent EGFR phosphorylation, but not by ERK inhibitor, PD98059. The inhibition of ERK, moreover, did not cause attenuation in phospholipid secretory responses to cAMP and forskolin. The findings underline the central role of EGFR in mediation of gastric mucosal secretory processes, and demonstrate the requirement for Src kinase-dependent EGFR transactivation in regulation of gastric mucosal phospholipid secretion in response to beta-adrenergic GPCR activation.     

Role of beta-adrenergic agonists in the control of vascular capacitance

The role of beta-adrenergic agonists, such as isoproterenol, on vascular capacitance is unclear. Some investigators have suggested that isoproterenol causes a net transfer of blood to the chest from the splanchnic bed. We tested this hypothesis in dogs by measuring liver thickness, cardiac output, cardiopulmonary blood volume, mean circulatory filling pressure, portal venous, central venous, pulmonary arterial, and systemic arterial pressures while infusing norepinephrine (2.6 micrograms.min-1.kg-1), or isoproterenol (2.0 micrograms.min-1.kg-1), or histamine (4 micrograms.min-1.kg-1), or a combination of histamine and isoproterenol. Norepinephrine (an alpha- and beta 1-adrenergic agonist) decreased hepatic thickness and increased mean circulatory filling pressure, cardiac output, cardiopulmonary blood volume, total peripheral resistance, and systemic arterial and portal pressures. Isoproterenol increased cardiac output and decreased total peripheral resistance, but it had little effect on liver thickness or mean circulatory filling pressure and did not increase the cardiopulmonary blood volume or central venous pressure. Histamine caused a marked increase in portal pressure and liver thickness and decreased cardiac output, but it had little effect on the estimated mean circulatory filling pressure. Isoproterenol during histamine infusions reduced histamine-induced portal hypertension, reduced liver size, and increased cardiac output. We conclude that the beta-adrenergic agonist, isoproterenol, has little influence on vascular capacitance or liver volume of dogs, unless the hepatic outflow resistance is elevated by agents such as histamine.     

Extra-long Gαs variant XLαs protein escapes activation-induced subcellular redistribution and is able to provide sustained signaling

Murine models indicate that Gαs and its extra-long variant XLαs, both of which are derived from GNAS, markedly differ regarding their cellular actions, but these differences are unknown. Here we investigated activation-induced trafficking of Gαs and XLαs, using immunofluorescence microscopy, cell fractionation, and total internal reflection fluorescence microscopy. In transfected cells, XLαs remained localized to the plasma membrane, whereas Gαs redistributed to the cytosol after activation by GTPase-inhibiting mutations, cholera toxin treatment, or G protein-coupled receptor agonists (isoproterenol or parathyroid hormone (PTH)(1-34)). Cholera toxin treatment or agonist (isoproterenol or pituitary adenylate cyclase activating peptide-27) stimulation of PC12 cells expressing Gαs and XLαs endogenously led to an increased abundance of Gαs, but not XLαs, in the soluble fraction. Mutational analyses revealed two conserved cysteines and the highly charged domain as being critically involved in the plasma membrane anchoring of XLαs. The cAMP response induced by M-PTH(1-14), a parathyroid hormone analog, terminated quickly in HEK293 cells stably expressing the type 1 PTH/PTH-related peptide receptor, whereas the response remained maximal for at least 6 min in cells that co-expressed the PTH receptor and XLαs. Although isoproterenol-induced cAMP response was not prolonged by XLαs expression, a GTPase-deficient XLαs mutant found in certain tumors and patients with fibrous dysplasia of bone and McCune-Albright syndrome generated more basal cAMP accumulation in HEK293 cells and caused more severe impairment of osteoblastic differentiation of MC3T3-E1 cells than the cognate Gαs mutant (gsp oncogene). Thus, activated XLαs and Gαs traffic differently, and this may form the basis for the differences in their cellular actions.     

Injections of beta-adrenergic substances in the locus coeruleus affect the gain of vestibulospinal reflexes in decerebrate cats

1. The tonic discharge of the noradrenergic locus coeruleus (LC) neurons is dampened by norepinephrine (NE) which acts not only on alpha2-adrenoceptors located on the somatodendritic membrane, through mechanisms of recurrent inhibition, but also on beta-receptors. Experiments were performed to find out whether inactivation of LC neurons by local injection of the beta-adrenergic agonist isoproterenol into the LC complex of one side produced changes in posture as well as in the gain of vestibulospinal reflexes acting on forelimb extensors. 2. In precollicular decerebrate cats the amplitude of modulation and thus the gain of the multiunit EMG responses of the forelimb extensor triceps brachii to animal tilt at 0.15 Hz, +/- 10 degrees, leading to sinusoidal stimulation of labyrinth receptors, were quite small. Microinjection of 0.25 microliter of a solution of the beta-adrenergic agonist isoproterenol at the concentration of 4.5-9.0 microgram/microliter of sterile saline into the LC complex of one side decreased the extensor rigidity in the ipsilateral limbs and to a lesser response gain of the ipsilateral triceps brachii to the same parameters of labyrinth stimulation greatly increased (t-test, P less than 0.001); moreover, a slight but significant increase in phase lead of the responses was observed. These findings appeared within 5-10 min after the injection of isoproterenol, fully developed within 20-30 min and persisted for about 2-3 hours after the injection. 3. The increased gain of the vestibulospinal reflexes acting on the triceps brachii did not depend on the decreased postural activity following injection of the beta-adrenergic agonist, since it was still observed if the reduced EMG activity of the extensor muscle following the injection was compensated for by an increased static stretch of the muscle. The positive correlation (t-test, P less than 0.001) between gain of the multiunit EMG response of the triceps brachii to animal tilt and base frequency observed in the control experiment disappeared and was substituted by a slight negative correlation (t-test, P less than 0.05) after injection of isoproterenol into the LC complex, probably due to a more prominent recruitment of motor units for low level of background discharge of the muscle. 4. In addition to the effects which involved the triceps brachii ipsilateral to the side of the injection, a smaller but significant increase in response gain affected the contralateral extensor muscle. This increase in gain was also associated with a slight increase in phase lead of the responses.(ABSTRACT TRUNCATED AT 400 WORDS)     

Metabolic effect of alpha-and the beta-adrenergic stimulation of rat submaxillary gland in vitro.

1. Incubation of submaxillary-gland slices with isoproterenol, a beta-adrenergic agonist, stimulated glucose removal by 41% and decreased tissue [glucose 6-phosphate] by 50%. Propranolol blocked these effects of isoproterenol. 2. Phenylephrine, an alpha-adrenergic agonist, stimulated glucose removal by 35% and decreased tissue [glucose 6-phosphate] by 75%. In addition, phenylephrine also completely overcame the inhibition of pyruvate removal caused by acetoacetate metabolism and decreased tissue [atp] by 45%. Phentolamine blocked the effects of phenylephrine. 3. In contrast with beta-adrenergic stimulation, alpha-adrenergic stimulation required exogenous Ca2+. 4. These results explain the different metabolic responses of the submaxillary gland to adrenaline in the presence and absence of exogenous Ca2+.     

N-Acetylation of Serotonin Is Correlated with α2- but Not with β-Adrenergic Regulation of Cyclic AMP Levels in Cultured Chick Pineal Cells

We investigated the role of cyclic AMP (cAMP) in alpha 2- and possible beta-adrenergic regulation of arylalkylamine-N-acetyltransferase (NAT), the penultimate enzyme in the biosynthesis of melatonin. The study was performed on primary cultures of dispersed chick pineal cells. Electron microscopy indicated that approximately 70% of the dispersed cells were modified photoreceptors. A similar proportion of melatoninergic cells was detected by immunocytochemical labeling of hydroxyindole-O-methyltransferase, the final enzyme in the biosynthesis of melatonin. Adrenergic agonists caused a sustained 50% inhibition of forskolin-augmented cAMP levels and NAT activity, with an alpha 2-adrenergic potency order of UK 14,304 greater than or equal to clonidine greater than norepinephrine greater than phenylephrine. Noradrenergic inhibition of 3-isobutyl-1-methylxanthine-augmented cAMP levels and NAT activity was reversed by yohimbine (an alpha 2-adrenergic antagonist) but not by prazosin (an alpha 1-adrenergic antagonist). The alpha-adrenergic inhibition of cAMP accumulation and NAT activity was prevented by pertussis toxin. Addition of propranolol (a beta-adrenergic antagonist) was necessary to observe an inhibitory effect of norepinephrine on cAMP levels but not on NAT activity. Similarly, the beta-adrenergic agonist isoproterenol transiently increased cAMP levels but did not affect NAT activity. The data indicate that the alpha 2-adrenergic inhibition of NAT activity in chick pineal cells is strongly correlated with an inhibition of cAMP accumulation. The lack of beta-adrenergic effect on NAT suggests that beta-adrenoceptors might be on a subset of cells that do not produce melatonin or that the beta-adrenergic-induced increase in cAMP levels is too transient to affect NAT.